Behavioral flexibility in a mouse model for obsessive-compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants

Genes Brain Behav. 2019 Apr;18(4):e12557. doi: 10.1111/gbb.12557. Epub 2019 Feb 27.


Obsessive-compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical-striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3-/- ) exhibit compulsive behavior (grooming), anxiety and dysregulated cortical-striatal function. However, it is unknown whether SAPAP3-/- display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3-/- and wild-type (WT) littermates were trained in a Pavlovian conditioning task pairing visual cues with the delivery of sucrose solution. After mice learned to discriminate between a reward-predicting conditioned stimulus (CS+) and a non-reward stimulus (CS-), contingencies were reversed (CS+ became CS- and vice versa). Additionally, we assessed grooming, anxiety and general activity. SAPAP3-/- acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3-/- were unable to adapt their behavior after contingency reversal, exemplified by a lack of re-establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming and anxiety were unrelated. This study shows that SAPAP3-/- are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3-/- not only display compulsive-like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3-/- as a suitable model for the study of OCD. The observation that compulsive-like behavior, anxiety and behavioral inflexibility were unrelated suggests a non-causal relationship between these traits and may be of clinical relevance for the treatment of OCD.

Keywords: Pavlovian conditioning; SAPAP3 mutant mice; anxiety; behavioral flexibility; cognitive flexibility; compulsive behavior; general activity; obsessive-compulsive disorder; reversal learning; symptoms relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Conditioning, Classical*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / genetics*
  • Obsessive-Compulsive Disorder / genetics
  • Obsessive-Compulsive Disorder / physiopathology*


  • Nerve Tissue Proteins
  • Sapap3 protein, mouse